This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Armet is a bifunctional protein apparently present in all multicellular animals. Inside cells, Armet is a relatively unstudied and relatively recently component of the Unfolded Protein Response to ER stress, and it is this aspect of Armet that our work focuses on. We are working on human Armet as a target for drug development, using non-labelled screening to find tight binding ligands, followed by detailed binding studies of hits from the primary screening and studies of the effects of these selected compounds on cells. The rationale underlying this work is that the action of Armet as a part of the cell's machinery for dealing with ER stress, if interfered with by tight-binding ligands, would render cells more susceptible to the apoptosis, a typical result of ER stress, but a fate often circumvented by cancer cells. In the KU High Throughput Screening Laboratory, a validation library of 10,000 compounds, most of which are biologically active, was screened last spring against human Armet, as expressed and purified in my laboratory. We have a group of approximately 20 "hits" from that screen, several of which are under active investigation now in my laboratory at Kansas State University, with favorable results in that secondary analysis of binding to Armet. The current proposal has the following aims: to screen an additional 100,000 compounds at the KU HTS Lab, using an ICx Technology instrument that will soon arrive in that lab;to conduct detailed binding studies of selected ligands by Surface Plasmon Resonance (Biacore 3000 at KSU) and in one case (gossypol) binding of a set of variants of the parent compound;and to examine, both in the HTS Lab and at KSU, the effect of tightest binding ligands on human cells having a wide range of malignant properties, looking specifically for compound that render cancer cells vulnerable to apoptosis. This will lead, in turn, in future work, to synthesis of chemical variants of a lead compound or compounds, seeking tighter binding to Armet while retaining desired effects on cancer cells.